Methods for treating allergic disorders using optically pure (-) cetirizine

ABSTRACT

Methods are disclosed utilizing optically pure (-) cetirizine for the treatment of seasonal and perennial allergic rhinitis in humans while avoiding the concomitant liability of adverse effects associated with the racemic mixture of cetirizine. The optically pure (-) isomer is also useful for the treatment of allergic asthma.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 08/167,724,filed Dec. 15, 1993, now abandoned, which is itself a continuation ofapplication Ser. No. 07/951,179, filed Sep. 24, 1992, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to novel compositions of matter containingoptically pure (-) cetirizine. These compositions possess potentactivity in treating seasonal and perennial allergic rhinitis, thesymptoms of allergic asthma, chronic idiopathic urticaria, some types ofphysical urticaria, and other disorders including those that wouldbenefit from an inhibitory action on eosinophil function. (-) Cetirizineinhibits eosinophil chemotaxis and function and the generation ofcytotoxic mediators by blood platelets, providing therapy inimmunologically-induced asthma with particular utility in the late phaseof the disease episode. Optically pure (-) cetirizine provides thistreatment while avoiding adverse effects, including, but not limited to,sedation and somnolence, headache, gastrointestinal disturbance,anticholinergic effects, dizziness, cardiac arrhythmias and othercardiovascular effects which are associated with the administration ofthe racemic mixture of cetirizine. Also disclosed are methods fortreating the above described conditions in a human while avoiding theadverse effects that are associated with the racemic mixture ofcetirizine by administering the (-) isomer of cetirizine to said human.

The active compound of these compositions and methods is an opticalisomer of cetirizine, the preparation of which is described in U.S. Pat.No. 4,525,358 (Baltes et al.). The medicinal chemistry of cetirizine isdescribed by Campoli-Richards et al., Drugs 40, 762-781 (1990)!, Snyderand Snowman Allergy 59 II, 4-8 (1987)!, and Rihoux and Dupont Annals ofAllergy 59, 235-238 (1987)!. Chemically, the active compound is the (-)isomer of 2- 4- (4-chlorophenyl)phenylmethyl!-1-piperazinyl)ethoxyacetic acid, hereinafter referred to as cetirizine.

(-) Cetirizine, which is the subject of the present invention, is notpresently commercially available; only the 1:1 racemic mixture iscommercially available as its dihydrochloride salt.

Many organic compounds exist in optically active forms, i.e.. they havethe ability to rotate the plane of plane-polarized light. In describingan optically active compound, the prefixes D and L or R and S are usedto denote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (-) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (-)or 1 meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. There is no correlation between nomenclaturefor the absolute stereochemistry and for the rotation of an enantiomer.Thus, D-lactic acid is the same as (-) lactic acid, and L-lactic acid is(+). For a given chemical structure, these chiral compounds exist as apair of enantiomers which are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomermay also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric or racemic mixture.

Stereochemical purity is of importance in the field of pharmaceuticals,where 12 of the 20 most prescribed drugs exhibit chirality. A case inpoint is provided by the L-form of the beta-adrenergic blocking agent,propranolol, which is known to be 100 times more potent than theD-enantiomer.

Furthermore, optical purity is important since certain isomers mayactually be deleterious rather than simply inert. For example, it hasbeen suggested that the D-enantiomer of thalidomide was a safe andeffective sedative when prescribed for the control of morning sicknessduring pregnancy, while the corresponding L-enantiomer has been believedto be a potent teratogen. The synthesis of (+) cetirizine and (-)cetirizine are described in British application 2,225,321, but nopharmacology of individual enantiomers is reported.

The racemic mixture of cetirizine is presently used primarily inseasonal and perennial allergic rhinitis. The symptomatology ofimmediate-type allergic diseases, including allergic rhinitis,presumably results from the antigen-induced release of variouspharmacologically active substances from mast cells, and from basophilicleukocytes. The substances thus released from these cells, and possiblyothers as well, are referred to as primary mediators of anaphylaxis andinclude, among others, histamine. The acute seasonal form of allergicrhinitis, hay fever, and perennial allergic rhinitis are characterizedby sneezing, rhinorrhea, nasal congestion, pruritus, conjunctivitis andpharyngitis. In acute seasonal rhinitis, the nose, roof of the mouth,eyes and pharynx often itch, and lacrimation, sneezing and clear, waterynasal discharge follow the pruritus. Additionally, frontal headaches,irritability, anorexia, depression and insomnia may occur. In perennialrhinitis, chronic nasal obstruction is often prominent and may extend toeustachian tube obstruction. For most patients, topical corticosteriods,some aerosol vasoconstrictor agents, and long acting antihistamineagents provide significant relief of symptoms. The action of cetirizineon non-immunologically (non IgE) mediated hypersensitivity reactions hasbeen less clear although there are some suggestions of activity in thetreatment of exercise induced asthma, cold urticaria, and non-specificbronchial hyperreactivity.

Racemic cetirizine dihydrocholoride is an orally active, potent, longacting peripheral histamine H₁ receptor antagonist. The compound is oneof the second generation of H₁ histamine receptor antagonists whichgenerally offer some significant advantages beyond the first generationcompounds. The advantages include (1) less sedation, (2) littleanticholinergic activity and (3) longer duration, which improves patientcompliance. In addition to being competitive inhibitors of histamine atthe end organ site, second generation H₁ histamine inhibitors appear tohave other anti-allergic pharmacologic mechanisms which have led totheir use in bronchial asthma, as well as in seasonal and perennialrhinitis and the chronic urticarias.

Experiments ex vivo suggest that racemic cetirizine does notsignificantly penetrate the blood brain barrier. It has been suggestedtherefore that cetirizine's ability to provide a reduced incidence ofsedative side effects may result in part from its receptor selectivityand in part from its relative exclusion from the CNS. Other experimentshave suggested that cetirizine does not inhibit mast cell activation butrather that it antagonizes the action of histamine once released fromthe mast cell following antigen or chemical stimulation. There are alsoreports that racemic cetirizine inhibits the degranulation of humanbasophils induced by anti IgE. Cetirizine has been shown to inhibit thechemotaxis of eosinophils to the tissues where they would otherwisecontribute to the pathogenesis of asthma.

Cetirizine is rapidly absorbed upon oral administration and althoughfood may slightly reduce the rate of absorption, the extent is notaffected. The compound is bound to plasma proteins and peak cetirizineconcentrations in the brain are less than 10% that of the plasmaconcentration. Cetirizine is excreted in the urine largely as unchangeddrug and the elimination half-life is roughly 7 to 10 hours.

The racemic mixture of cetirizine may be useful in treating otherdisorders such as allergic pulmonary disease and particularly intreating the symptoms of allergic bronchial asthma. Patients who sufferfrom allergic bronchial asthma develop such clinical symptoms aswheezing and dyspnea after exposure to allergens, environmentalirritants, viral infections, cold air and exercise. Many of the symptomsresult from smooth muscle contraction and vascular dilatation, which, inturn, result from mediator release when the antigen reacts with the IgEantibody on the surface of a mast cell or basophil. This serves as abasis for the use of histamine H₁ antagonists.

In addition, racemic cetirizine may be useful for treating chronicidiopathic urticaria and some types of physical urticaria. Urticaria ischaracterized by local wheals and erythema in the dermis; acuteurticaria is essentially an anaphylaxis that is limited to the skin andsubcutaneous tissues. The condition may arise from food allergy, drugallergy, insect sting, or the like, and is distinct from chronic oridiopathic urticaria which may last for several weeks and can onlyrarely be associated with a specific cause. Because these urticariasappear in many cases to be IgE antibody mediated, many of the symptomsmay be treated with a histamine H₁ receptor antagonist such ascetirizine. The direct inhibition of eosinophil chemotaxis by cetirizinemay also provide therapy to the late phase of allergic episodes indisorders such as allergic asthma, allergic rhinitis, and in otherconditions characterized by eosinophilia.

Many of the second generation histamine H₁ receptor antagonists offeradvantages over the first generation of histamine antagonists in thatthere is reduced sedation and anticholinergic activity. Nonetheless,some adverse effects remain, including, but not limited to, someincidence of sedation and somnolence; cardiovascular effects includingarrhythmias; headache; gastrointestinal disturbances; dizziness andnausea. The racemic mixture of cetirizine has been found to cause manyof these adverse effects, including sedation and somnolence. Thus, itwould be particularly desirable to find a compound with the advantagesof the racemic mixture of cetirizine which would not have theaforementioned disadvantages.

SUMMARY OF THE INVENTION

It has now been discovered that the optically pure (-) isomer ofcetirizine is an effective agent for treating seasonal and perennialallergic rhinitis, the symptoms of allergic asthma, chronic idiopathicurticaria, some physical urticaria, and other disorders, including thosethat would benefit from an inhibitory action on eosinophilia, andeosinophil function. The optically pure (-) isomer of cetirizineprovides this effective treatment while avoiding the adverse effectsincluding, but not limited to, sedation and somnolence, headache,gastrointestinal disturbance, dizziness, nausea, cardiac arrhythmias andother cardiovascular effects. The present invention also includesmethods for treating the above described conditions in a human whileavoiding the adverse effects that are associated with the racemicmixture of cetirizine by administering the optically pure (-) isomer ofcetirizine to said human.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a method of treating the symptoms ofseasonal and perennial allergic rhinitis in a human, which comprisesadministering to a human in need of such symptomatic relief therapy, anamount of (-) cetirizine, or a pharmaceutically acceptable salt thereof,substantially free of its (+) stereoisomer, said amount being sufficientto alleviate the symptoms of seasonal and perennial allergic rhinitis.The method avoids the concomitant liability of adverse effectsassociated with the administration of the racemic compound by providingan amount which is insufficient to cause the adverse effects associatedwith the racemic mixture of cetirizine.

The present invention also encompasses an antirhinitis composition forthe treatment of a human in need of antirhinitis therapy, whichcomprises an amount of (-) cetirizine, or a pharmaceutically acceptablesalt thereof, substantially free of its (+) stereoisomer, said amountbeing sufficient to alleviate said rhinitis but insufficient to causethe adverse effects associated with racemic cetirizine.

The present invention further encompasses a method of treating allergicasthma and chronic and physical urticaria in a human, which comprisesadministering to a human in need of such asthma or urticaria therapy, anamount of (-) cetirizine, or a pharmaceutically acceptable salt thereof,substantially free of its (+) stereoisomer, sufficient to alleviate saidasthma or urticaria. The method avoids the concomitant liability ofadverse effects associated with the administration of racemic cetirizineby providing an amount which is insufficient to cause adverse effectsassociated with the administration of racemic cetirizine.

In addition, the present invention encompasses an antiallergic andantiurticaric composition for the treatment of a human having allergicasthma, chronic idiopathic urticaria and some types of physicalurticaria, which comprises an amount of (-) cetirizine, or apharmaceutically acceptable salt thereof, substantially free of its (+)isomer, said amount being sufficient to alleviate or palliate saiddisorder but insufficient to cause adverse effects associated with theadministration of racemic cetirizine.

A further aspect of the present invention includes a method of treatinga condition caused by or contributed to by eosinophilia or enhancedeosinophil function in a human, which comprises administering to a humanin need of such therapy, an amount of (-) cetirizine, or apharmaceutically acceptable salt thereof, substantially free of its (+)stereoisomer, sufficient to alleviate said eosinophilia or enhancedeosinophilia function. The method avoids the concomitant liability ofadverse effects associated with the administration of racemic cetirizineby providing an amount which is insufficient to cause adverse effectsassociated with the administration of racemic cetirizine. Conditionsassociated with an eosinophilia or an altered eosinophil function inhumans may include, but are not limited to, allergic asthma, seasonalallergic rhinitis, atopic dermatitis, some parasitic diseases, andchronic obstructive lung disease with no demonstrable evidence ofallergic asthma. Moreover accumulations of eosinophils in both thegastrointestinal and genitourinary tracts indicate the desirability ofregulation of eosinophil function in disorders of these tracts.

Furthermore, the present invention includes a composition for treatingdisorders associated with or enhanced by an eosinophilia or enhancedeosinophil function that would benefit from a potent inhibitor ofeosinophil chemotaxis in a human which comprises an amount of (-)cetirizine, or a pharmaceutically acceptable salt thereof, substantiallyfree of its (+) stereoisomer, said amount being sufficient to alleviatesaid condition associated with an eosinophilia or altered eosinophilfunction, but insufficient to cause adverse effects associated with theadministration of racemic cetirizine.

The available racemic mixture of cetirizine (i.e. a 1:1 racemic mixtureof the two enantiomers) exhibits antihistaminic activity through itsselective and potent binding to histamine H₁ peripheral receptor sitesand causes inhibition of eosinophil chemotaxis thus providing therapyand a reduction of symptoms in a variety of conditions and disordersrelated to allergic rhinitis, allergic asthma, several types ofurticaria, and conditions related to eosinophilia; however, this racemicmixture, while offering the expectation of efficacy, causes adverseeffects. Utilizing the optically pure or substantially optically pureisomer of (-) cetirizine results in enhanced efficacy, diminishedadverse effects, and accordingly, an improved therapeutic index. It istherefore, more desirable to use the (-) isomer of cetirizine than toadminister the racemic mixture.

The term "adverse effects" includes, but is not limited to, sedation andsomnolence, headache, gastrointestinal disturbance, dizziness, nausea,cardiac arrhythmias and other cardiovascular effects.

The term "substantially free of its (+) stereoisomer" as used hereinmeans that the compositions contain a greater proportion of the (-)isomer of cetirizine in relation to the (+) isomer of cetirizine. In apreferred embodiment, the term "substantially free of its (+) isomer" asused herein means that the composition comprises at least 90% by weightof (-) cetirizine and 10% by weight or less of (+) cetirizine. In a morepreferred embodiment the term "substantially free of the (+) isomer"means that the composition contains at least 99% by weight of (-)cetirizine, and 1% or less of (+) cetirizine. In the most preferredembodiment, the term "substantially free of its (+) stereoisomer" asused herein means that the composition contains greater than 99% byweight of (-) cetirizine. These percentages are based upon the totalamount of cetirizine in the composition. The terms "substantiallyoptically pure (-) isomer of cetirizine" or "substantially opticallypure (-) cetirizine" and "optically pure (-) isomer of cetirizine" and"optically pure (-) cetirizine" are also encompassed by theabove-described amounts.

The term "treating the symptoms of seasonal and perennial rhinitis" asused herein means treating, alleviating or palliating such conditions,and thus providing relief from the symptoms of sneezing, rhinorrhea,nasal congestion, pruritus, conjunctivitis, pharyngitis, lacrimation,frontal headaches, irritability, anorexia, depression, insomnia,eustachian tube obstruction, and the like.

The term "a method for treating allergic asthma and chronic and physicalurticaria in a human" as used herein means treating, alleviating orpalliating such conditions, and thus providing relief from the symptomsof wheezing, dyspnea, coughing, shortness of breath, respiratory mucushypersecretion, airway inflammation, local cutaneous wheals, erythema,and the like.

The term, "treating a condition caused by, or contributed to, byeosinophilia, or enhanced eosinophil function in a human" as used hereinmeans treating, alleviating or palliating such disorders associated withan eosinophilia, thus providing relief from the symptoms of theaforementioned conditions. Allergic asthma, seasonal allergic rhinitis,atopic dermatitis, chronic obstructive lung disease, and symptomsassociated with some parasitic diseases, gastrointestinal andgenitourinary disorders are among the conditions caused by orcontributed to by eosinophilia.

The chemical synthesis of the racemic mixture of cetirizine can beperformed by the method described in U.S. Pat. No. 4,525,358 cited aboveor by an improved procedure disclosed in British application 2,225,320.The (-) isomer of cetirizine may be obtained from its racemic mixture byresolution of the enantiomers of cetirizine or precursors thereto usingconventional means such as an optically active resolving acid. Forexample, British application 2,225,321 (Cossement et al.), which isincorporated herein by reference, discloses a method for resolving the1- (4-chlorophenyl)phenylmethyl!piperazine precursor using tartaric acidin ethanol. Other standard methods of resolution known to those skilledin the art including, but not limited to, simple crystallization andchromatographic resolution, can be used. (See for example, E. L. Eliel,Stereochemistry of Carbon Compounds, McGraw Hill (1962) and Wilen andLochmuller "Tables of Resolving Agents" Journal of Chromatography 113,283-302 (1975)!. Additionally, the optically pure (-) isomer can beprepared from the racemic mixture by enzymatic biocatalytic resolution.See for example U.S. Pat. Nos. 5,057,427 and 5,077,217, the disclosuresof which are incorporated herein by reference.

The magnitude of a prophylactic or therapeutic dose of (-) cetirizine inthe acute or chronic management of disease will vary with the severityof the condition to be treated and the route of administration. The doseand perhaps the dose frequency will also vary according to the age, bodyweight and response of the individual patient. In general, the totaldaily dose range for (-) cetirizine for the conditions described hereinis from about 1.0 mg to about 25 mg in single or divided doses.Preferably a daily dose range should be about 2.0 mg to about 20 mg insingle or divided doses while most preferably a daily dose range shouldbe about 5 mg to about 10 mg in single or divided doses. In managing thepatient, the therapy should be initiated at a lower dose, perhaps atabout 2 mg to about 5 mg and increased up to about 10 mg or higherdepending on the patient's global response. It is further recommendedthat children and patients over 65 years and those with impaired renalor hepatic function, initially receive low doses, and that they betitrated based on individual response(s) and blood level(s). It may benecessary to use dosages outside these ranges in some cases as will beapparent to those skilled in the art. Further, it is noted that theclinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patientresponse. The terms "an amount sufficient to alleviate or palliatesymptoms of seasonal and perennial allergic rhinitis but insufficient tocause said adverse effects," "an amount sufficient to alleviate orpalliate the symptoms of allergic asthma and chronic and physicalurticaria but insufficient to cause said adverse effects" and "an amountsufficient to alleviate or palliate the symptoms arising from theeosinophilia of allergic asthma, seasonal allergic rhinitis, atopicdermatitis, parasitic diseases, chronic obstructive lung disease,gastrointestinal and genitourinary disorders but insufficient to causesaid adverse effects" are encompassed by the above-described dosageamounts and dose frequency schedule.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of (-) cetirizine. For example, oral,rectal, parenteral (subcutaneous, intramuscular, intravenous),transdermal, and like forms of administration may be employed. Dosageforms include tablets, troches, dispersions, suspensions, solutions,capsules, patches, and the like.

The pharmaceutical compositions of the present invention comprise (-)cetirizine as the active ingredient, or a pharmaceutically acceptablesalt thereof, and may also contain a pharmaceutically acceptablecarrier, and optionally, other therapeutic ingredients.

The terms "pharmaceutically acceptable salts" or "a pharmaceuticallyacceptable salt thereof" refer to salts prepared from pharmaceuticallyacceptable non-toxic acids or bases including inorganic acids and basesand organic acids and bases. Since the compound of the present inventionis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids including inorganic and organic acids. Suitablepharmaceutically acceptable acid addition salts for the compound of thepresent invention include acetic, benzenesulfonic (besylate), benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like.

The compositions of the present invention include suspensions,solutions, elixirs, aerosols, or solid dosage forms. Carriers such asstarches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders, disintegrating agents, and the like aresuitable in the case of oral solid preparations (such as powders,capsules, and tablets), and oral solid preparations are preferred overthe oral liquid preparations. The most preferred oral solid preparationis a tablet.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are employed. If desired, tablets may be coatedby standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofthe present invention may also be administered by controlled releasemeans and delivery devices such as those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, thedisclosures of which are hereby incorporated by reference.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets, tablets, or aerosol sprays, each containing a predeterminedamount of the active ingredient, as a powder or granules, or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Suchcompositions may be prepared by any of the methods of pharmacy, but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation.

For example, a tablet may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active agent ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet contains from about 2 mg to about10 mg of the active ingredient, and each cachet or capsule contains fromabout 2 mg to about 10 mg of the active ingredient. Most preferably, thetablet, cachet or capsule contains either one of three dosages, about 2mg, about 5 mg and about 10 mg of (-) cetirizine dihydrochloride fororal administration.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of the compound and thecompositions of the present invention, as well as their utility. It willbe apparent to those skilled in the art, that many modifications, bothto materials, and methods, may be practiced without departing from thepurpose and interest of this invention.

EXAMPLES Example 1

The antihistaminic activity of the racemate and enantiomers ofcetirizine is studied in receptor binding assays with washed guinea pigbrain and lung tissue membranes following the procedure of Snyder andSnowman (op cit). The tissues are used to establish inhibitoryconcentration values expressed in micromolar concentration (IC₅₀) forracemic cetirizine and its enantiomers to inhibit the binding oftritiated mepyramine. The selection of these tissues providesinformation as to the binding at central and peripheral H₁ histaminereceptors. The specificity of the H₁ -receptor binding may then becompared with the binding at radio ligand labeled receptors for othercentral mediators.

Example 2

The antihistaminic activity of the isomers of cetirizine is also studiedin vitro in the guinea pig ileum preparation described by StaffPharmacological Experiments on Isolated Preparations, E & S. LivingstoneLtd., Edinburgh (1968).!

Example 3

Cetirizine isomer activity is also studied in isolated guinea pigtracheobronchial smooth muscle preparation according to the method ofCampoli-Richards, et al. Drugs 40, 762-781 (1990)! and Wardell, et al.J. Pharm. Exp. Ther. 167-184 (1974)!. These preparations demonstratecompetitive antagonism to histamine-induced contractions in a modelrelevant to the inhibition of histamine-induced disorders in vivo. Theprimary antihistaminic activity is then compared to the relativeanticholinergic activities ("adverse effects") of cetirizine in the sametissue. The anticholinergic activity is evaluated by challenging thetissue with a cholinergic agent.

Example 4

Single ventricular myocytes are obtained from isolated cat hearts byconventional techniques. The rod-shaped single cells are maintained in aHEPES buffer and they are "patch clamped" using suction pipettes. APatch-Clamp L/M-PEC 7 amplifier is used to record current tracings, andthe recording electrodes are filled with a solution of potassiumaspartate. Voltage clamp pulses and data acquisition are controlled by aSperry PC/IT Computer running P Clamp software. A minimum of 4 cells arestudied at each test concentration of the following drugs: racemiccetirizine, (+) cetirizine, (-) cetirizine and quinidine (as a referencecompound).

    ______________________________________                                        ORAL FORMULATION                                                              Capsules:                                                                                 Quantity per capsule in mg                                        Formula       A           B       C                                           ______________________________________                                        (-) Cetirizine                                                                              2.0         5.0     10.0                                        Lactose       103.75      100.75  95.75                                       Cornstarch    18.75       18.75   18.75                                       Magnesium Stearate                                                                          0.50        0.50    0.50                                        Compression Weight                                                                          125.0       125.0   125.0                                       ______________________________________                                    

The (-) cetirizine, lactose and cornstarch are blended until uniform andthen the magnesium stearate is blended into the resulting powder, whichis sieved and filled into suitably sized, two-piece, hard gelatincapsules using conventional machinery. Other doses may be prepared byaltering the fill weight and, if necessary, changing the capsule size tosuit.

    ______________________________________                                        ORAL FORMULATION                                                              Tablets:                                                                                 Quantity per tablet in mg                                          Formula      A          B         C                                           ______________________________________                                        (-) Cetirizine                                                                             2.0        5.0       10.0                                        Lactose      70.75      67.75     62.75                                       Cornstarch   3.0        3.0       3.0                                         Water        30.0 mL    30.0 mL   30.0 mL                                     (per thousand Tablets)*                                                       Cornstarch   18.75      18.75     18.75                                       Magnesium Stearate                                                                         0.50       0.50      0.50                                        Compression Weight                                                                         125.0      125.0     125.0                                       ______________________________________                                         *The water evaporates during manufacture                                 

The (-) cetirizine is blended with the lactose until a uniform blend isformed. The smaller quantity of cornstarch is blended with the water toform the resulting corn starch paste. This is then mixed with theuniform blend until a uniform wet mass is formed. The remainingcornstarch is added to the resulting wet mass and mixed until uniformgranules are obtained. The granules are then screened through a suitablemilling machine, using a 1/4 inch stainless steel screen. The milledgranules are dried in a suitable drying oven until the desired moisturecontent is obtained. The dried granules are then milled through asuitable milling machine, magnesium stearate is blended in, and theresulting mixture is compressed into tablets of the desired shape,thickness, hardness and disintegration. Tablets of other strengths maybe prepared by altering the ratio of active ingredient to the excipientsor to the final weight of the tablet.

What is claimed is:
 1. A method of treating the symptoms of seasonal andperennial allergic rhinitis in a human which comprises administering toa human in need of such symptomatic relief therapy an amount of (-)cetirizine, or a pharmaceutically acceptable salt thereof, substantiallyfree of its (+) stereoisomer, said amount being sufficient to alleviateor palliate said allergic rhinitis.
 2. A method of treating the symptomsof seasonal and perennial allergic rhinitis in a human, while avoidingthe concomitant liability of sedation associated with racemiccetirizine, which comprises administering to a human in need of suchsymptomatic relief therapy an amount of (-) cetirizine, or apharmaceutically acceptable salt thereof, substantially free of its (+)stereoisomer, said amount being sufficient to alleviate or palliate saidallergic rhinitis but insufficient to cause said sedation.
 3. The methodof claim 2 wherein (-) cetirizine is administered by intravenousinfusion or orally as a tablet or a capsule.
 4. The method of claim 3wherein the amount of (-) cetirizine or a pharmaceutically acceptablesalt thereof administered is from about 1 mg to about 25 mg per day. 5.The method of claim 4 wherein the amount administered is from about 2 mgto about 20 mg per day.
 6. The method of claim 5 wherein the amountadministered is from about 5 mg to about 10 mg per day.
 7. The method ofclaim 2 wherein the amount of (-) cetirizine or a pharmaceuticallyacceptable salt thereof is greater than approximately 90% by weight ofthe total weight of cetirizine.
 8. The method of claim 2 wherein theamount of said (-) cetirizine or a pharmaceutically acceptable saltthereof, substantially free of its (+) stereoisomer, is administeredtogether with a pharmaceutically acceptable carrier.
 9. The methodaccording to claim 2, wherein (-) cetirizine is administered as ahydrochloride salt.
 10. A method of treating allergic asthma in a humanwhich comprises administering to a human in need of such therapy anamount of (-) cetirizine, or a pharmaceutically acceptable salt thereof,substantially free of its (+) stereoisomer, said amount being sufficientto alleviate symptoms of allergic asthma.
 11. A method of treatingallergic asthma in a human, while avoiding the concomitant liability ofsedation associated with racemic cetirizine, which comprisesadministering to a human in need of such therapy an amount of (-)cetirizine, or a pharmaceutically acceptable salt thereof, substantiallyfree of its (+) stereoisomer, said amount being sufficient to alleviatesymptoms of allergic asthma but insufficient to cause said sedation. 12.The method of claim 11 wherein (-) cetirizine is administered byintravenous infusion or orally as a tablet or a capsule.
 13. The methodof claim 12 wherein the amount of (-) cetirizine or a pharmaceuticallyacceptable salt thereof administered is from about 1 mg to about 25 mgper day.
 14. The method of claim 13 wherein the amount administered isfrom about 2 mg to about 20 mg per day.
 15. The method of claim 14wherein the amount administered is from about 5 mg to about 10 mg perday.
 16. The method of claim 11 wherein the amount of (-) cetirizine ora pharmaceutically acceptable salt thereof is greater than approximately90% by weight of the total weight of cetirizine.
 17. The method of claim11 wherein the amount of said (-) cetirizine or a pharmaceuticallyacceptable salt thereof, substantially free of its (+) stereoisomer, isadministered together with a pharmaceutically acceptable carrier. 18.The method according to claim 11, wherein (-) cetirizine is administeredas a hydrochloride salt.